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First published online January 23, 2009
doi: 10.1242/10.1242/dev.027748

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Sall genes regulate region-specific morphogenesis in the mouse limb by modulating Hox activities

¹ Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
² Stem Cell Institute, University of Minnesota, 2001 6th SE, Minneapolis, MN. 55455, USA.
³ Department of Genetics, Cell Biology and Development, 6-160 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455, USA.
⁴ Developmental Biology Center, University of Minnesota, 321 Church St. SE, Minneapolis, MN 55455, USA.
⁵ Division of Integrative Cell Biology, Institute of Molecular Embryology and Genetics, Global COE `Cell Fate Regulation Research and Education Unit', Kumamoto University, Kumamoto, Japan 860-0811.
⁶ Department of Neuroscience, University of Minnesota, 321 Church St. SE, Minneapolis, MN 55455, USA.
⁷ Center of Regenerative Medicine in Barcelona, Doctor Aiguader, 88, 08003 Barcelona, Spain.
⁸ Laboratory of Genetics and Development, Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal, 110 avenue des Pins Ouest, H2W 1R7, Montréal, Quebec, Canada.
⁹ Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.

^* Author for correspondence (e-mail: belmonte{at}salk.edu)

Accepted 8 December 2008

The genetic mechanisms that regulate the complex morphogenesis of generating cartilage elements in correct positions with precise shapes during organogenesis, fundamental issues in developmental biology, are still not well understood. By focusing on the developing mouse limb, we confirm the importance of transcription factors encoded by the Sall gene family in proper limb morphogenesis, and further show that they have overlapping activities in regulating regional morphogenesis in the autopod. Sall1/Sall3 double null mutants exhibit a loss of digit1 as well as a loss or fusion of digit2 and digit3, metacarpals and carpals in the autopod. We show that Sall activity affects different pathways, including the Shh signaling pathway, as well as the Hox network. Shh signaling in the mesenchyme is partially impaired in the Sall mutant limbs. Additionally, our data suggest an antagonism between Sall1-Sall3 and Hoxa13-Hoxd13. We demonstrate that expression of Epha3 and Epha4 is downregulated in the Sall1/Sall3 double null mutants, and, conversely, is upregulated in Hoxa13 and Hoxd13 mutants. Moreover, the expression of Sall1 and Sall3 is upregulated in Hoxa13 and Hoxd13 mutants. Furthermore, by using DNA-binding assays, we show that Sall and Hox compete for a target sequence in the Epha4 upstream region. In conjunction with the Shh pathway, the antagonistic interaction between Hoxa13-Hoxd13 and Sall1-Sall3 in the developing limb may contribute to the fine-tuning of local Hox activity that leads to proper morphogenesis of each cartilage element of the vertebrate autopod.

Key words: Sall, Townes-Brocks syndrome, Hox, Limb development, Shh, Eph, Mouse

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